Download Automatic injection device with torsional spring

US 20130096513A1
(19) United States
(12) Patent Application Publication (10) Pub. No.: US 2013/0096513 Al
Smith
(43) Pub. Date:
(54) AUTOMATIC INJECTION DEVICE WITH
(30)
Apr. 18, 2013
Foreign Application Priority Data
TORSIONAL SPRING
Jul. 8, 2010
(75) Inventor:
(EP) ................................ .. 10168927.1
Christopher James Smith, Cheshire
(GB)
Publication Classi?cation
(73) Assignee: SANOFI-AVENTIS DEUTSCHLAND
GMBH, Frankfurt am Main (DE)
(21) Appl. No.:
13/579,081
(22)
PCT Filed:
Feb. 15, 2011
PCT N .:
PCT/EP2011/052226
(51)
Int- Cl
A61M 5/315
(2006.01)
(52) US. Cl.
CPC ................................. .. A61M5/3155 (2013.01)
86
( )
O
USPC ........................................................ .. 604/211
(57)
ABSTRACT
§ 371 (0X1),
(2), (4) Date? Dec- 27, 2012
Related US‘ Application Data
A semi-automatic “?xed” dose injection device is disclosed
containing a reservoir of medicament, Where a trigger con
Provisional application No. 61/305,436, ?led on Feb.
17, 2010.
mined injection of medicament from the reservoir through a
trols the unWmdmg of a tors1onal spring to cause a predeter
(60)
disposable needle.
W1
Patent Application Publication
Apr. 18, 2013 Sheet 1 0f 2
US 2013/0096513 A1
Patent Application Publication
Apr. 18, 2013 Sheet 2 0f 2
US 2013/0096513 A1
Apr. 18, 2013
US 2013/0096513 A1
AUTOMATIC INJECTION DEVICE WITH
TORSIONAL SPRING
needle by the action of stored energy, preferably from a, e.g.
Wound, dose spring, Within the device. The user, hoWever,
may have to manually insert the needle before the injection,
CROSS REFERENCE TO RELATED
APPLICATIONS
remove the needle after the injection, and/or activate the
trigger in order to complete the injection. The user may also
have to “recharge” the dose spring betWeen doses. This may
[0001] The present application is a US. National Phase
Application pursuant to 35 U.S.C. §371 of International
Application No. PCT/EP2011/052226 ?led Feb. 15, 2011,
Which claims priority to US. Provisional Patent Application
No. 61/305,436 ?led on Feb. 17, 2010 and European Patent
Application No. 10168927.1 ?led Jul. 8, 2010. The entire
disclosure contents of these applications are herewith incor
porated by reference into the present application.
FIELD OF INVENTION
[0002] This disclosure relates to a “?xed” dose injection
device that may deliver a predetermined dose of medicament
from a cartridge preferably through a single needle, particu
larly semi-automatically, When a user activates a trigger.
BACKGROUND
be accomplished as part of the dose setting procedure. Energy
may be stored in the dose spring during dose setting, Which
energy may be released for injecting the dose.
[0011] Using the “?xed” dose mechanism of this disclosure
it is possible to con?gure the mechanism Where the ?xed dose
is anyWhere betWeen 0.01 ml to approximately 0.30 ml (1
insulin unit to about 30 insulin units). Because the disclosed
device delivers only a predetermined ?xed dose, the dose dial
may have only markings for the single predetermined ?xed
dose. No other dose markings are needed. The user may rotate
the dose dial to the marking for the ?xed dose Whereupon the
dose dial clicks as a ratchet on the drive shaft engages a gear
tooth on the gear. At this point the dose dial expediently
remains in the “set” position. The user may be prevented from
dialing doses smaller than the ?xed dose by the action of the
Multi-use and disposable injection devices are in
dose spring, e. g. a torsion action. If the user does not rotate the
common use for the delivery of injected medication. Such
dose dial suf?ciently to engage the dose dial ratchet, then as
devices are needed so that a user may take repeated doses of
soon as the user releases the dose dial the dose spring Will
rotate the dose dial back to the Zero unit position. The user
[0003]
a medication at speci?c time intervals, for example rapid
acting or basal insulins, GLP-l, heparin, etc. Conducting
repeated injections is both inconvenient and confusing to
some users, especially those users With visual imparity or
cognitive de?ciencies.
[0004]
Accordingly, them is a strong need to provide inj ec
tion devices that are easy to use and that alloW a user to set a
predetermined “?xed” dose of a medicament.
[0005] It is an object of this disclosure to provide a novel
injection device, preferably an improved injection device.
[0006] This object may be achieved by the subject matter of
the independent claims. Advantageous embodiments and
re?nements are the subject matter of the dependent claims.
[0007]
This disclosure facilitates solving the above-de
scribed problems, for example, by providing a, preferably
semi-automatic, injection device Were the user can only dial
predetermined doses of medicament. These and other advan
tages Will become evident from the folloWing more detailed
description of the invention.
[0008] The claimed subject matter does have various
advantages Which, inter alia, Will become apparent from the
description beloW.
[0012]
The setting of the ?xed predetermined dose may be
controlled by the interaction of the gear, the trigger, and the
drive shaft, Which may be, preferably permanently, connected
to the dose dial. During dose setting the gear may be pre
vented from rotation by the trigger. The trigger may have a set
of teeth on an inner surface that engages complementary teeth
on the outer side of the gear. The drive shaft preferably has a
ratchet arm that engages one or more limited number of teeth,
Which are preferably equally spaced an angle 0t from each
other. The teeth may be provided on the proximal side and/or
on an inner surface of the gear. Preferably, this angle 0t is at
least about 20 degrees, most preferably in the range of about
30 degrees to about 180 degrees. The minimum end of the
preferable range may be determined by the smallest rotation
that can be easily distinguished by the user so it is clear
Whether or not a dose has been set. The maximum end of the
preferable range may be determined by the greatest rotation
that a user can comfortably achieve in one single movement
Without signi?cantly altering their grip during dose setting.
SUMMARY
[0009]
may be prevented from dialing larger doses by one or more
mechanical stops limiting the travel of the dose dial.
According to an exemplary arrangement the injec
tion device of this disclosure, for example a ?xed dose inj ec
tion device, is a multiple use device, meaning that a number of
injections can be administered from the same medicament
container or cartridge until that container is empty. The device
may be made as a disposable variant Where the entire device
is discarded once the medicament container is empty, or as a
reusable variant, Where the user can discard and replace the
empty medicament container and reuse the device mecha
nism. For each separate inj ection the user may manually
attach a neW sterile needle. After the injection this needle may
be manually removed and discarded.
[0010] The injection device of this disclosure may be a
“semi-automatic” injection device. This means that the liquid
medication Will be delivered automatically through the
For example, a 120 degrees rotation may be more comfortable
for a user, but 180 degrees is also possible. Furthermore, the
angle 0t is preferably a divisor of 360 degrees so that the teeth
may be evenly spaced around the inner side of the gear. In
variable dose injectors, each tooth on the inner side of a gear
usually corresponds to one index of the dose dial, for
example, 0.01 ml (1 insulin unit) for a 21 unit con?guration or
0.02 ml (2 insulin units) for a 42 unit version. In these non
?xed dose devices, the angle betWeen the teeth is alWays less
than 16 degrees. This is in contrast to this disclosure Where the
angle 0t is preferably alWays greater than about 20 degrees.
When dialing a dose in these prior art devices the user rotates
the dose dial and the drive shaft ratchet clicks over the desired
number of teeth. In this manner a number of different doses
could be set each time the device is used. This is preferably
not possible in the ?xed dose device of this disclosure, Which
requires rotation to overcome only a single tooth to set the
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US 2013/0096513 A1
same “?xed” predetermined dose each time the device is
used. Preferably, a rotation Which may overcome more than
one tooth is prevented.
[0013] Rotating the dose dial may also store energy, e.g.
torsional energy, Within the dose spring. When the trigger is
activated, e.g. pressed, the trigger and the gear may disen
gage. Particularly, the teeth on the gear, preferably outer teeth
on the gear, may disengage from the corresponding teeth on
the trigger and the gear becomes free to rotate. The dose
spring may drive the drive shaft in rotation, Which in turn
preferably rotates the gear, particularly, because the ratchet
arm is engaged With teeth of the gear, preferably inner teeth of
the gear. The gear may have one or more internal threads that
are engaged With one or more external threads of the plunger.
The pitch [3 of the respective thread, preferably of the threads
of the plunger and/or of the gear, may be selected and
matched so that rotation of the gear, Which is expediently
constrained in the axial direction, Will cause the non-rotating
plunger to move axially. Preferably, the angle 0t and the pitch
[3 are selected so that the axial advance of the plunger is set to
a particular value corresponding to the desired ?xed dose. The
axial advance of the plunger may be determined by the cal
culation:
[0014] More speci?cally, angle 0t is preferably in the range
from about 30 degrees to about 180 degrees. The pitch [3 of a
thread on plunger and/or gear is preferably from about 1.5
mm to about 12 mm. Expressed differently, it is preferred that
the ratio of ot/ [3 is in the range from about 10 to about 20
degrees/mm.
[0015] Preferably the limited number of teeth on the gear
that dictate or contribute to the “?xed” predetermined dose
are evenly spaced around the circumference of the gear. The
angle 0t betWeen these teeth preferably corresponds to the
angle that the drive shaft Will be rotated When the ?xed dose
is delivered. For example, if the gear contains four teeth then
the angle 0t betWeen them Will be 90°. If the drive plunger
set any dose beloW the “?xed dose” determined by the spacing
of the gear teeth. The fact that the dose dial immediately
rotates back to Zero units, rather than remaining at the marker
for the ?xed dose, Will alert the user to the fact that the dose
Was not properly set. This should prevent the user from
attempting to deliver a Zero dose. This places an ergonomic
limit on hoW far the user can be expected to rotate the dose dial
in one movement. It is therefore preferred that there should be
a minimum of tWo gear teeth. This Would mean that the
maximum rotation the user Would have to apply Would be
1 80°.
[0017] The maximum dose of the device may be limited by
adding features that Will limit the rotation of the dose dial (and
hence drive shaft). This rotation limit, Will be designed to
ensure that the user Will alWays be able to dial the ratchet arm
beyond one gear tooth (irrespective of any manufacturing
tolerances) and not beyond a second tooth. In practice this
means that the rotation stop may be set in the region 0t to 2a
and With suf?cient clearance to ensure that the effect of manu
facturing variability does not take the rotation stop outside of
this range. Preferably the rotation stop Will be set toWards the
loWer end of the range so that the user does not dial signi?
cantly beyond the ?rst gear tooth. A small amount of over
rotation is required in order to guarantee that the ratchet arm
Will engage. Therefore, the rotational limit of the dose dial
Would be set to an angle slightly greater than the angle 0t
betWeen the gear teeth. HoWever, this over travel does not
contribute to any dose accuracy error of the pen because When
the user releases the dose dial the dose spring Will immedi
ately rotate the dose dial and drive shaft back until the ratchet
arm contacts the gear tooth. Given that the trigger is not
pressed at this point then the rotation of the drive shaft does
not rotate the gear and hence no medicament is dispensed. A
number of options exist for adding rotation restricting fea
tures, for example features could be added to the dose dial and
the body, or to the drive shaft and the body.
[0018]
The plunger may be prevented from rotation by
thread pitch [3 is 6 m then a 90° rotation Will cause the
plunger to advance by a “?xed” increment of 1.5 mm. By
features in a reset dial, preferably ?ngers that engage ?ats
along the axis of the plunger. Therefore, rotation of the gear
appropriate design of the number of gear teeth, and the thread
pitch [3 betWeen the gear and the plunger, the nominal volume
of the ?xed dose can be altered. A particular advantage of
may cause the plunger to advance along its threaded connec
devices disclosed herein over prior art devices is that small
doses (for example doses<0.05 ml or 5 insulin units) can be
delivered With improved dose accuracy. This may be achieved
by the combination of large angles 0t and small thread pitch [3.
Large angles of 0t mean that any angular error (?x example
variability due to the manufacturing tolerances, eg of either
gear or ratchet arm) represents only a small percentage of the
angle 0t. Combining this With small values of thread pitch [3
Will produce the small advance of plunger necessary for
delivering small doses. A further advantage of the larger angle
of 0t is that the, preferably torsional, spring, Which Will pro
vide the energy required for automatic dose delivery, is
loaded over a longer movement. This means that the dialing
torque that the user must apply to charge the spring With a
given amount of energy is reduced compared to a device With
a smaller value of 0t.
[0016] As mentioned, if the user fails to rotate the dose dial
by an angle suf?cient to engage the ratchet arm of the drive
shaft, then the dose Will not be set. The dose spring Will rotate
the dose dial and drive shaft back to the Zero unit position of
the dose dial. Therefore, it Will be impossible for the user to
tion to the gear and this dispenses liquid from the medicament
container as it moves a piston or bung in the distal direction.
If the trigger is released at any point during the delivery of the
dose a trigger spring may force the teeth on the trigger to
reengage the gear, preferably to reengage outer teeth on the
gear, and cause delivery to stop. Pressing the trigger again
Will continue the delivery, until the dose has been delivered.
[0019] A further advantage of devices disclosed herein over
the prior art is that the trigger and gear may be con?gured so
that the trigger only needs a single activation to delivery the
full “?xed” dose, Without requiring the user to hold the trigger
in the active position. Variable dose devices usually have a
trigger that can re-engage With the gear at any point that
corresponds to a multiple of the smallest dose that the user can
dial and deliver, ie if the inner surface of the gear (Which
engages the ratchet arm) has 24 gear teeth then the outer
surface of the gear (Which engages the trigger) must also have
24 gear teeth. Therefore, once the dose delivery has been
initiated the user may release the trigger button at any time
during dose delivery and the delivery Will stop. The possibil
ity of stopping the dose delivery may lead to dose errors
Where the user mistakenly or deliberately delivers an incom
plete dose.
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US 2013/0096513 A1
[0020] A further embodiment of the proposed ?xed dose
device seeks to improve the usability of the device so that the
entire dose is delivered With one push of the trigger, eg a
trigger button, irrespective of Whether the trigger is held. This
is accomplished by modifying the trigger mechanism. The
setting stage. This may use larger sets of muscles, arms and
Wri sts rather than ?nger or thumb poWer, and should therefore
be easier for patients. Also, the energy is applied before the
needle is injected into the body. Therefore, it does not matter
if there is some movement or shaking of the device.
teeth of the gear and the trigger may be replaced by a set of
[0024]
male & female features, e. g. teeth and grooves, on the gear &
sible that the user does not press the dose dial fully inWards
trigger. The features Would be equally spaced around the
circumference of the gear and the number of features Would
and therefore may deliver an under dose. With a semi-auto
matic device of this disclosure the full dose is achieved more
match the number of dose setting teeth of the gear/ drive shaft
interface. The proposed features Would make it impossible
require pressing a manual dose button can cause the user to
for the trigger to re-engage the gear until the gear has com
pleted its ?xed rotation. Therefore, the user Would press the
trigger once to start the delivery, and then the complete dose
Would deliver automatically, irrespective of Whether the user
holds the trigger or not. Because the trigger may automati
cally slide back into place at the end of the dose, e.g. driven by
the trigger spring, the user Will receive visual con?rmation
that the dose has been fully delivered. In addition the trigger
could be designed to click When it re-engages the gear, pro
viding audible con?rmation as Well.
[0021] After the medicament container has been emptied
the user Will be able to reset the plunger to its initial position
and a neW medicament container can then be loaded into the
device and the device can be reused.
[0022] A titrationpen variant of the ?xed dose device of this
disclosure is also possible. In this variant the maximum rota
tion of the dose is not limited to alloWing the ratchet arm to
rotate beyond only one gear tooth. Instead the maximum
rotation is designed to alloW the ratchet arm to rotate beyond
multiple gear teeth. This number of teeth that the ratchet arm
may rotate past Would correspond to the number of “titration”
doses that the user desired to set. The titration device may be
con?gured to alloW 5 or less, eg 3 or less, titration doses to
be set by a user. For example, if the device Were designed such
that a 90° rotation of the plunger delivers a dose of 5 units and
the gear Was designed With 4 gear teeth then the ratchet arm
Would engage a gear tooth every 90°. Setting the maximum
rotation of the dose dial to 270° Would enable three different
doses to be set by the user: 5 units, 10 units or 15 units. To
reach the 15 unit dose the user Would turn the dose dial
through 3 clicks of the drive shaft ratchet, corresponding to
270°. HoWever, unlike the single ?xed dose device this could
be achieved by the user in a number of steps. It is therefore not
necessary to limit total rotation to 1800 (although each sub
In prior knoWn manually driven devices it is pos
consistently. LikeWise, dose accuracy in prior devices that
not behave consistently Where they Will press and hold the
button for varying times. Different button hold times alloW
different expansion of the bung or piston, e. g. a rubber bung or
a rubber piston, Within the medicament container or cartridge
and this has the potential to create variability betWeen doses.
The semi-automatic feature of devices disclosed herein elimi
nates this variable because the dose spring Will Work inde
pendently of the user, particularly during the injection. There
fore, the forces applied to the bung or piston of the
medicament container during dose delivery may be deter
mined by the design of the device, irrespective of forces
applied to the trigger button.
[0025] In the folloWing text, a set of particularly advanta
geous aspects of the injection device is provided by making
use of numbers to facilitate making references to the respec
tive aspects.
[0026] 1. A ?xed dose injection device comprising the fol
loWing in combination,
[0027]
a. a housing; and
[0028] b. a dose setting/injecting assembly comprising,
[0029]
i. a rotatable gear having at least tWo teeth offset
from an each other at an angle 0t that corresponds to a
predetermined ?xed dose of medicament, Where the gear
Wheel is ?xed axially in the housing;
[0030] a plunger threadedly engaged With the rotatable
gear having a pitch [3 that is matched With angle 0t so that
the plunger moves distally during dose delivery a dis
tance equal to the predetermined dose;
[0031] iii. a torsional spring, and a drive shaft; and
[0032]
iv. a trigger connected to the rotatable gear such
that When the trigger is activated the torsional spring
unWinds and causes the gear Wheel to rotate through
angle 0t and to move the plunger distally to deliver the
predetermined ?xed dose.
dose dialed should be less than 180°). In the titration embodi
ment delivery of doses in betWeen the ?xed titration doses is
[0033] 2. The injection device of aspect 1 Wherein a medi
cament housing is connected to the housing and holds a
prevented in a similar manner as preventing under doses for
the ?xed dose device. If the user dials a dose in betWeen the
cartridge of medicament.
[0034] 3. The injection device of aspect 1 Wherein the angle
?xed titration doses the dose spring Will rotate the dose dial
0t is from about 20 degrees to about 180 degrees.
and the drive shaft back until the ratchet arm engages at the
[0035] 4. The injection device of aspect 1 Wherein the ratio
of ot/[3 is in the range from about 10 to about 20 degrees/mm.
[0036] 5. An ?xed dose titration infection device compris
next gear tooth, corresponding to the next loWest titration
dose. The set dose Would be clearly displayed to the user by
the dose dial, so it Would be clear that the higher dose had not
ing the folloWing in combination,
been set.
[0037]
[0023] A semi-automatic feature of devices disclosed
herein has certain advantages over knoWn delivery devices
that rely on a user’s manual pressing of an injection button.
[0038] b. a dose setting/injecting assembly comprising,
This creates dif?culty or even pain for elderly use or those
With reduced manual dexterity. Also, any shaking of the hand
While pressing the dose button Will cause movement of the
device and needle, making the injection more painful. A
[0039]
a. a housing; and
i. a rotatable gear having at least a ?rst, a second,
and a third tooth offset from an each other at an angle 0t
that corresponds to a predetermined ?xed dose of medi
cament, Where the gear Wheel is ?xed axially in the
housing;
[0040]
ii. a drive shaft having a ratchet arm that is con
semi-automatic device removes this problem. The user sup
?gured engage either the ?rst, the second or the third
plies the energy to provide the injection during the dose
tooth during dose setting;
Apr. 18, 2013
US 2013/0096513 A1
[0041] iii. a plunger threadedly engaged With the rotat
able gear having a of pitch [3 that is matched With angle
0t so that the plunger moves distally during dose delivery
a distance equal to one or more multiples of the prede
termined dose;
[0042]
iv. a torsional spring; and
[0043]
v. a trigger connected to the rotatable gear such
that When the trigger is activated the torsional spring
unWinds and causes the gear Wheel to rotate through
angle 0t and to move the plunger distally to deliver the
predetermined ?xed dose;
[0044]
Features describe above orbeloW in connection With
different aspects, embodiments etc. may, of course, be com
bined With features described in connection With other
aspects, embodiments etc. or With a combination of such
features even if such a combination is not explicitly described
herein.
[0045] The advantages mentioned above as Well as other
advantages of various aspects of the present disclosure Will
become apparent to those of ordinary skill in the art by read
ing the folloWing detailed description, With appropriate ref
erence to the accompanying draWings.
BRIEF DESCRIPTION OF THE FIGURES
[0046] Exemplary embodiments are described herein With
reference to the draWings, in Which:
[0047] FIG. 1 illustrates one possible embodiment of the
“?xed” dose injection device of this disclosure;
[0048] FIG. 2 illustrates a cross sectional vieW through the
“?xed” dose injection device of this disclosure shoWing a
?xed dose stationary gear, the drive shaft and ratchet arm
engaging one of the four teeth on the inner surface of the gear;
and
[0049] FIG. 3 illustrates possible embodiments of the drive
shaft, gear and trigger of the dose setting assembly of this
disclosure.
DETAILED DESCRIPTION
[0050]
A schematic cross section of one embodiment of the
“?xed” dose injection device 1 of this disclosure is illustrated
in FIG. 1. The device comprises tWo main assemblies; a dose
setting/inj ecting assembly; and a cartridge holder 4. The
device comprises a body 3. The dose setting/inj ecting assem
bly may be at least partly retained or housed in body 3. The
dose setting and cartridge holder assemblies are similar in
design and operation to that described in US. Pat. No. 5,104,
380 With signi?cant differences. One signi?cant difference is
that the disclosed device is con?gured to alloW the user to set
only a ?xed, predetermined dose, as opposed to a large num
ber of different doses. This difference in operation may result
from a novel design of gear 10. This novel design of the gear
is best vieWed in FIG. 2.
[0051] A cartridge 23 is retained in the cartridge holder. A
piston 17 may be arranged and movably retained in the car
tridge 23. The cartridge 23 expediently holds a medicament
Which is to be dispensed from the device 1. The piston 17 may
seal the medicament Within the cartridge 23.
[0052] The term “medicament”, as used herein, preferably
means a pharmaceutical formulation containing at least one
pharmaceutically active compound,
[0053] Wherein in one embodiment the pharmaceutically
active compound has a molecular Weight up to 1500 Da
and/ or is a peptide, a proteine, a polysaccharide, a vaccine, a
DNA, a RNA, an enZyme, an antibody, a hormone or an
oligonucleotide, or a mixture of the above-mentioned phar
maceutically active compound,
[0054] Wherein in a further embodiment the pharmaceuti
cally active compound is useful for the treatment and/or pro
phylaxis of diabetes mellitus or complications associated
With diabetes mellitus such as diabetic retinopathy, throm
boembolism disorders such as deep vein or pulmonary throm
boembolism, acute coronary syndrome (ACS), angina, myo
cardial infarction, cancer, macular degeneration,
in?ammation, hay fever, atherosclerosis and/or rheumatoid
arthritis,
[0055] Wherein in a further embodiment the pharmaceuti
cally active compound comprises at least one peptide for the
treatment and/ or prophylaxis of diabetes mellitus or compli
cations associated With diabetes mellitus such as diabetic
retinopathy.
[0056] Wherein in a further embodiment the pharmaceuti
cally active compound comprises at least one human insulin
or a human insulin analogue or derivative, glucagon-like pep
tide (GLP-l) or an analogue or derivative thereof, or exedin-3
or exedin-4 or an analogue or derivative of exedin-3 or exe
din-4.
[0057] Insulin analogues are for example Gly(A21), Arg
(B31), Arg(B32) human insulin; Lys(B3) Glu(B29) human
insulin; Lys(B28), Pro(B29) human insulin; Asp(B28) human
insulin; human insulin, Wherein praline in position B28 is
replaced by Asp, Lys, Leu, Val or Ala and Wherein in position
B29 Lys may be replaced by Pro; Ala(B26) human insulin;
Des(B28-B30) human insulin; Des(B27) human insulin and
Des(B30) human insulin.
[0058]
Insulin derivates are for example B29-N-myristoyl
des(B30) human insulin; B29-N-palmitoyl-des(B30) human
insulin; B29-N-myristoyl human insulin; B29-N-palmitoyl
human insulin; B28-N-myristoyl LysB28ProB29 human
insulin; B28-N-palmitoyl-LysB28ProB29 human insulin;
B30-N-myristoyl-ThrB29LysB30 human insulin; B30N
palmitoyl-ThrB29LysB30 human insulin; B29-N-(N-palmi
toyl-Y-glutamyl)-des(B30) human insulin; B29-N-(N-litho
cholyl-Y-glutamyl)-des(B30) human insulin; B29-N-(uu
carboxyheptadecanoyl)-des(B30) human insulin and B29-N
(uu-carboheptadecanoyl) human insulin.
[0059]
Exendin-4 for example means Exendin-4(1-39), a
peptide of the sequence HiHis4GlyiGlu4GlyiThri
PheiThriSeriAspiLeuiSeriLys4GlniMeti
Glu4Glu4GluiAlaiValiArgiLeuiPheiIlei
GluiTrpiLeuiLysiAsn4Gly4GlyiProiSeri
Ser4GlyiAlaiProiProiProiSeriNHZ.
[0060]
Exendin-4 derivatives are for example selected from
the folloWing list of compounds:
Hi(Lys)4-des Pro36, des Pro37 Exendin-4(1-39)-NH2,
Hi(Lys)5-des Pro36, des Pro37 Exendin-4(1-39)-NH2,
des Pro3 6 [Asp28] Exendin-4(1-3 9),
des Pro36 [IsoAsp28] Exendin-4(1-39),
Apr. 18, 2013
US 2013/0096513 A1
des Pro36 [Met(O)14, Asp28] Exendin-4(1-39),
des Pro3 6 [Met(O) 14, lsoAsp28] Exendin-4(1-3 9),
des Pro3 6 [Trp(O2)25, Asp28] Exendin-4(1-3 9),
des Pro36 [Trp(O2)25, lsoAsp28] Exendin-4(1-39),
des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39),
des
Pro36
[Met(O)14
Trp(O2)25,
lsoAsp28]
H-Asn-(Glu)5 -des Pro36, Pro37, Pro3 8 [Met(O) 14, Asp28]
Exendin-4(1-3 9) -NH2,
des
Pro3 6,
Pro37,
Pro3 8
[Met(O)14,
Asp28]
Exendin-4(1-3 9)-(Lys)6-NH2,
H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exen
din-4(1-39)-(Lys)6-NH2,
Exendin-4(1-3 9); or
des Pro3 6 [Asp28] Exendin-4(1-3 9),
H-Asn-(Glu)5 des Pro3 6, Pro37, Pro3 8 [Met(O) 14, Asp28]
des Pro36 [lsoAsp28] Exendin-4(1-39),
H-Lys6-des Pro36 [Met(O)14, Trp(O2)25, Asp28] Exendin
Exendin-4(1-3 9)-(Lys)6-NH2,
des Pro36 [Met(O)14, Asp28] Exendin-4(1-39),
des Pro3 6 [Met(O) 14, lsoAsp28] Exendin-4(1-3 9),
des Pro3 6 [Trp(O2)25, Asp28] Exendin-4(1-3 9),
des Pro3 6 [Trp(O2)25, Asp28] Exendin-4(1-3 9),
des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39),
des
Pro36
[Met(O)14
Trp(O2)25,
lsoAsp28]
4(1-39)-Lys6-NH2,
H-des Asp28 Pro3 6, Pro37, Pro3 8 [Met(O)14, Trp(O2)25]
Exendin-4(1-3 9) -NH2,
H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exen
din-4(1-39)-NH2,
H-Asn-(Glu)5 -des Pro3 6, Pro37, Pro3 8 [Met(O)14, Trp (O2)
Exendin-4(1-3 9),
25, Asp28] Exendin-4(1-3 9)-NH2,
[0061] wherein the group -Lys6-NH2 may be bound to the
C-terminus of the Exendin-4 derivative;
Exendin-4(1-39)-(Lys)6-NH2,
or an Exendin-4 derivative of the sequence
H-(Lys)6-des Pro36 [Asp28] Exendin-4(1-39)-Lys6-NH2,
des Asp28 Pro36, Pro37, Pro38Exendin-4(1-39)-NH2,
H-(Lys)6-des Pro36, Pro38 [Asp28] Exendin-4(1-39)-NH2,
H-Asn-(Glu)5des Pro36, Pro37, Pro38 [Asp28]
Exendin-4(1-3 9) -NH2,
des
Pro36,
Pro37,
Pro3 8
[Asp28]
Exendin-4(1-3 9)-(Lys)6-NH2,
H-(Lys)6-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1
39)-(Lys)6-NH2,
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Asp28] Exendin-4
(1-39)-(Lys)6-NH2,
H-(Lys)6-des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39)
Lys6-NH2,
H-des
Asp28
Pro36,
M037,
Pro38
[Trp(O2)25]
Exendin-4(1-3 9) -NH2,
H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]
Exendin-4(1-3 9) -NH2,
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]
Exendin-4(1-3 9) -NH2,
des
Pro36,
Pro37,
Pro38
[Trp(O2)25,
Asp28]
Exendin-4(1-3 9)-(Lys)6-NH2,
H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]
des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28]
H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25,
Asp28] Exendin-4(S1-39)-(Lys)6-NH2,
H-Asn-(Glu)5 -des Pro3 6, Pro37, Pro3 8 [Met(O)14, Trp (O2)
25, Asp28] Exendin-4(1-3 9)-(Lys)6-NH2;
[0063] or a pharmaceutically acceptable salt or solvate of
any one of the afore-mentioned Exedin-4 derivative.
[0064]
Hormones are for example hypophysis hormones or
hypothalamus hormones or regulatory active peptides and
their antagonists as listed in Rote Liste, ed. 2008, Chapter 50,
such as Gonadotropine (Follitropin, Lutropin, Choriongona
dotropin, Menotropin), Somatropine (Somatropin), Desmo
pressin, Terlipressin, Gonadorelin, Triptorelin, Leuprorelin,
Buserelin, Nafarelin, Goserelin.
[0065] A polysaccharide is for example a glucosaminogly
cane, a hyaluronic acid, a heparin, a loW molecular Weight
heparin or an ultra loW molecular Weight heparin or a deriva
tive thereof, or a sulphated, eg a poly-sulphated form of the
above-mentioned polysaccharides, and/or a pharmaceuti
cally acceptable salt thereof. An example of a pharmaceuti
cally acceptable salt of a poly-sulphated loW molecular
Weight heparin is enoxaparin sodium.
[0066]
Pharmaceutically acceptable salts are for example
acid addition salts and basic salts. Acid addition salts are e.g.
HCl or HBr salts. Basic salts are e.g. salts having a cation
selected from alkali or alkaline, e.g. Na+, or K+, or Ca2+, or
an ammonium ion N+(R1)(R2)(R3)(R4), Wherein R1 to R4
Exendin-4(1-3 9)-(Lys)6-NH2,
independently of each other mean hydrogen, an optionally
substituted C1-C6-alkyl group, an optionally substituted
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]
C2-C6-alkenyl group, an optionally substituted C6-C10-aryl
Exendin-4(1-3 9)-(Lys)6-NH2,
group, or an optionally substituted C6-C10-heteroaryl group.
H-(Lys)6-des Pro36 [Met(O)14, Asp28] Exendin-4(1-39)
Lys6-NH2,
Pro37,
Pro38
des Met(O)14 Asp28 Pro36,
Exendin-4(1-3 9) -NH2,
[0062] H-(Lys)6-desPro36, Pro37, Pro38 [Met(O)14,
Asp28] Exendin-4(1-39)-NH2,
Further examples of pharmaceutically acceptable salts are
described in “Remington’s Pharmaceutical Sciences” 17. ed.
Alfonso R. Gennaro (Ed.), Mark Publishing Company, Eas
ton, Pa., U.S.A., 1985 and in Encyclopedia of Pharmaceutical
Technology.
[0067]
Pharmaceutically acceptable solvates are for
example hydrates.
Apr. 18, 2013
US 2013/0096513 A1
[0068] A disposable injection needle assembly (not shown)
on piston 17 inside cartridge 23. This causes the pressure in
is attached to hub 2, Which preferably has external threads that
the cartridge to increase and liquid medicament is dispensed
engage similar pitch threads inside a female hub on the dis
from the distal end of the cartridge into an attached needle.
posable needle assembly. The setting of the ?xed dose Within
injection device 1 is controlled by the interaction of the drive
shaft 9, Which is preferably permanently connected to dose
dial 5, and gear 10, Which is expediently slidably engaged
With trigger 6. During dose setting, gear 10 is prevented from
The pitch [3 may be 6 mm, for example, resulting in an axial
displacement of the plunger by 1.5 mm When the gear is
rotated by the angle 0t of 90°. If the trigger 6 is released at any
point during the delivery of the set dose, teeth 15 and 16 Will
re-engage stopping the rotation of gear 10 and thus stopping
the delivery of medicament. When the trigger 6 is being held
by the user in the activated position a trigger spring 8 may
tend to push the trigger 6 into re-engagement With gear teeth
rotation by the interaction of components on the gear and
trigger. Drive shaft 9 features a ratchet arm 12 (see FIG. 2)
that engages teeth 11 on an inner surface 14 of gear 10. Each
tooth 11 is separate by an angle 0t from the next tooth, shoWn
15 on the outside of the gear 10. When the trigger 6 is released
in FIG. 2 as 90°. Each tooth of the gear corresponds to one
predetermined ?xed dose. By appropriate design of the num
by the user, the trigger spring 8 Will re-engage trigger and
gear. Pres sing the trigger again Will continue the delivery until
ber of gear teeth, as described above, and the thread pitch
betWeen the gear and the plunger, the nominal volume of the
medicament is complete When the dose dial 5 reaches a rota
?xed dose can be altered.
tional stop (not explicitly shoWn) With respect to the body 3.
[0069]
This stop position corresponds to the “Zero dose selected”
position of the dose dial 5.
Movement of the plunger 7 is achieved by energy
stored in a helical torsional spring 18, Which is tWisted as the
dose of medicament to be injected from the cartridge 23 is set
by rotation of dose dial 5. The dose dial can turn about a
graduated sleeve or the drive shaft and may contain printed
graduations that correspond to the ?xed dose. Body 3 can
have a lens or one or more WindoWs (not explicitly shoWn)
through Which graduations on the sleeve or shaft can be read
to shoW that the ?xed dose has been set.
[0070]
When dialing a dose the user rotates dose dial 5,
Which causes the connected drive shaft 9 and ratchet arm 12
to rotate and click over one of the teeth 11 in gear 10. The user
may rotate the dose dial by the angle 0t or an angle Which is
slightly greater than 0t. The user may be prevented from
rotating the dose dial 5 by 2a by a rotational stop (not explic
itly shoWn) Which may be provided in the body, for example.
Thus, setting of a dose exceeding the ?xed dose may be
prevented. Alternatively, instead of providing a ?xed dose
device Where only one dose may be dialed, a titration device
may be provided as described further above, Which is
designed such that a limited number, eg 5 or less, preferably
3 or less, titration doses may be dialed by the user. Rotating
the dose dial also stores torsional energy Within the corre
sponding dose spring 18 that is fastened to the dose dial. This
stored torsional energy is used to automatically deliver the
medicament dose When trigger 6 is pressed or otherWise
activated causing the spring 18 to unWind and returning the
dose dial 5 and the drive shaft 9 to the initial Zero position.
When the trigger 6 is activated, teeth 16 disengage from teeth
15 on gear 10 and the gear becomes free to rotate With drive
shaft 9 (see FIG. 3).
[0071]
The stored energy of the dose spring 18 drives the
drive shaft 5 in rotation, Which in turn rotates the gear 10. The
gear 10 has a central threaded opening 22 that is in threaded
all of the dialed units have been delivered. The injection of
[0072] If the user fails to rotate the dose dial by an angle
suf?cient to engage the ratchet arm 12 of the drive shaft 9,
then the dose Will not be set. The dose spring Will rotate the
dose dial and drive shaft back to the Zero unit position of the
dose dial. Therefore, it Will be impossible for the user to set
any dose beloW the “?xed dose” determined by the spacing of
the gear teeth
[0073] Upon injection, axial movement of the plunger 7
along the quick pitch thread, Which may be provided in open
ing 22, accompanies rotation of gear 10 and drive shaft 9 since
the plunger 7 cannot rotate in the reset dial 13. Thus, the
plunger is driven into the cartridge. expelling the ?xed dose of
medicament from the cartlidge. The injection of medicament
is complete When dose dial 5 reaches a rotational stop (not
explicitly shoWn) With respect to the body 3. The stop position
corresponds to the “Zero dose selected” position of dose dial
5. When the dose dial 5 reaches its rotational stop on the pen
body, the plunger remains part-Way along the inside of the
cartridge. The procedure can be repeated until the cartridge is
exhausted, after Which the cartridge can be replaced by
removing the cartridge holder from the dose dialing assem
bly.
[0074]
In some cases, the requirement to hold doWn the
trigger until the injection is complete may be considered
undesirable and therefore an alternate embodiment Would
include a con?guration that prevents the trigger from reen
gaging With the gears even though the user releases the trig
ger. This may, for example, be accomplished by including a
detent mechanism Whereby pressing the trigger causes it to
bump-over a detent so that it Will remain in the forWards
position even if the user releases the trigger, eg a trigger
button. The detent could be designed to disengage only When
engagement With plunger 7. The plunger is prevented from
the drive shall or dose dial have returned to their initial, Zero,
rotation by features in reset dial 13. Preferably, the reset dial
positions. This Would enable the complete injection to be
delivered With only a single press of the trigger (Without the
need to hold the trigger forWards). A further advantage Would
13 contains tWo protrusions (not shoWn) that consist of
opposed ?ats that engage tWo longitudinal grooves on
opposed sides along the length of the drive plunger 7. When
the corresponding cartridge holder 4 is attached to the body 3,
the reset dial 13 is prevented from rotation relative to the body
3. Thus, When the cartridge holder 4 is connected to the body
3, rotation of the drive plunger 7 is prevented. Because the
be that the return of the trigger to its initial position Would
give the user additional visual and audible feedback to indi
cate that the dose is complete.
[0075] Alternatively or additionally, the ?xed dose device
may be con?gured so that the entire dose is delivered With one
drive plunger 7 cannot rotate and the gear 10 cannot move
push of the trigger 6, eg a trigger button, irrespective of
axially, the rotation of the gear 10 causes the drive plunger 7
Whether the trigger is held or detented as described above.
to advance along its thread having pitch [3 that is engaged With
This may be accomplished by modifying the trigger mecha
the thread in gear 10 in an axial distal direction exerting force
nism. The teeth 15 of the gear 10 and the teeth 16 of the trigger
Apr. 18, 2013
US 2013/0096513 A1
6 may be replaced by a set of male and female features (not
explicitly shown), e.g. teeth and grooves, on the gear 10 and
on the trigger 6. The features may be equally spaced around
the circumference of the gear 10. The number of features
preferably matches the number of gear teeth 11. These fea
tures are preferably designed such that it is impossible for the
trigger 6 to re-engage the gear 10 until the gear has completed
its ?xed rotation for delivering the ?xed dose. Therefore, the
user Would press the trigger 6 once to start the delivery, and
then the complete dose may be delivered automatically, irre
spective of Whether the user holds the trigger 6 or not.
Because the trigger 6 may automatically slide back into place
at the end of the dose, e.g. driven by the trigger spring 8, the
user Will receive visual con?rmation that the dose has been
fully delivered.
[0076]
The reset dial 13 not only prevents the plunger from
iv. a trigger connected to the rotatable gear such that
When the trigger is activated the torsional spring
unWinds and causes the rotatable gear to rotate
through angle 0t and to move the plunger distally to
deliver the predetermined ?xed dose; and
v. a rotation stop that limits the rotation of the drive shaft,
preventing a rotation beyond more than one tooth of
the rotatable gear.
9: The injection device of claim 8 Wherein a medicament
housing is connected to the housing and holds a cartridge of
medicament.
10: The injection device of claim 8 Wherein the angle 0t is
from 20 degrees to 180 degrees.
11: The injection device of claim 8 Wherein the ratio of 01/[3
is in the range from 10 to 20 degrees/mm.
12: The injection device of any of claim 8 Wherein the pitch
rotation during that movement, but it also acts as a means ?x
[3 ofa thread on the plunger is from 1.5 mm to 12 mm.
retracting the drive plunger 7 back into the body 3 thus reset
ting the device. When the cartridge holder 4 is attached to the
body 3 the reset dial 13 is restrained against rotation in the
comprises a ratchet arm that engages one of the teeth during
13: The injection device of claim 8 Wherein the drive shaft
dose setting.
body 3 by a locking member (not explicitly shoWn) ?tted into
14: The injection device of claim 8 Wherein the drive shaft
the reset dial 13. When the cartridge holder 4 is removed the
locking member is unrestrained and alloWs rotation of the
reset dial 13. The drive plunger 7 may be prevented from
rotation relative to the reset dial 13 by the engagement of reset
comprises a ratchet arm that is con?gured to engage one of the
teeth during dose setting.
15: A ?xed dose titration injection device comprising the
folloWing in combination,
dial protrusions and drive plunger longitudinal moves (not
a. a housing; and
explicitly shoWn). The drive plunger 7 is threadedly engaged
b. a dose setting and injecting assembly comprising,
to the gear 10, Which is ?xed in rotation relative to the body 3
by the engagement of gear teeth 15 and trigger teeth 16.
i. a rotatable gear having at least a ?rst, a second, and a
third tooth offset from each other at an angle 0t that
Rotation of the reset dial 13 causes the drive plunger 7 to
rotate Which causes it to Wind up the thread in the gear 1 0, thus
corresponds to a predetermined ?xed dose of medi
cament, Where the rotatable gear is ?xed axially in the
retracting the drive plunger 7 back into the body 3.
[0077] Exemplary embodiments of the present disclosure
have been described. Those skilled in the art Will understand,
hoWever, that changes and modi?cations may be made to
these embodiments Without departing from the true scope and
spirit of the subject matter, Which is de?ned by the claims.
1-7. (canceled)
8: A ?xed dose injection device comprising the folloWing
in combination,
a. a housing; and
b. a dose setting and injecting assembly comprising,
i. a rotatable gear having at least tWo teeth offset from
each other at an angle 0t that corresponds to a prede
termined ?xed dose of medicament Where the rotat
able gear is ?xed axially in the housing;
ii. a plunger threadedly engaged With the rotatable gear
having a pitch [3 that is matched With angle 0t so that
the plunger moves distally during dose delivery a
distance corresponding to the predetermined ?xed
dose;
iii. a torsional spring, and a drive shaft Wherein the
torsional spring rotates the drive shaft back to a Zero
position if the drive shaft is rotated by an angle
smaller than 0t;
housing;
ii. a drive shaft having a ratchet arm that is con?gured to
engage either the ?rst, the second or the third tooth
during dose setting;
iii. a plunger threadedly engaged With the rotatable gear
having a pitch [3 that is matched With angle 0t so that
the plunger moves distally during dose delivery a
distance corresponding to one or more multiples of
the predetermined ?xed dose;
iv. a torsional spring Wherein the torsional spring rotates
the drive shaft back until the ratchet arm engages at
the next gear tooth, corresponding to the next loWer
dose, if a dose is dialled in betWeen tWo ?xed titration
doses; and
v. a trigger connected to the rotatable gear such that
When the trigger is activated the torsional spring
unWinds and causes the rotatable gear to rotate
through one or more multiples of angle 0t and to move
the plunger distally to deliver the one or more mul
tiples of the predetermined ?xed dose,
vi. a rotation stop that limits the rotation of the drive
shaft, preventing a rotation beyond a limited number
of teeth of the rotatable gear.
*
*
*
*
*